Insulin like growth factor 1 (IGF-1) stimulates proliferation and inhibits apoptosis, thereby affecting the development and progression of a variety of epithelial tumors, including breast cancer. Cell culture experiments have identified two major signaling pathways that mediate the effects of IGF-1 on cellular transformation and proliferation in vitro. Studies show that both pathways are involved in crosstalk with the estrogen receptor (ER) and enhance receptor activity through phosphorylation of specific serine residues. Transgenic models also demonstrate the importance of IGF-1 in mammary development and tumorigenesis. However, many models utilize hormonally- or pregnancy-induced promoters that preclude analysis of ER crosstalk or the impact of hormonal manipulation. We have initiated studies with a new BK5.IGF-1 transgenic model in which the K5 promoter is constitutively and not hormonally regulated and directs transgene expression to the myoepithelial cells in the mammary gland. The myoepithelial or basal layer lies adjacent to the ductal epithelium and is composed of specialized cells with both epithelial and muscular characteristics. Thus, this model allows assessment of hormonal contributions to IGF-1-promoted mammary tumorigenesis and also recapitulates the paracrine exposure of ductal epithelial cells to locally produced growth factor. Preliminary studies with the BK5.IGF-1 model indicate that paracrine/juxtacrine exposure to IGF-1 stimulates ductal hyperplasia and renders the glandular epithelium significantly more susceptible to DMBA-initiated carcinogenesis. Signaling analyses show that transgenic tumors have increased activation of the PI3K-Akt pathway compared to wild type tumors. Preliminary studies also demonstrate that mammary adenocarcinomas express functional ER as detected at both the message and protein level. The goal of the proposed studies is to test the hypothesis that IGF-1 stimulates mammary tumorigenesis in vivo predominantly through activation of the PI3K-Akt pathway and requires downstream activation of ER (crosstalk). A corollary hypothesis, that IGF-1-mediated activation of ER contributes to tamoxifen resistance, will also be addressed in the proposed studies. The following specific aims will be performed: 1) Investigate the contribution of the PI3K-Akt pathway to mammary tumorigenesis in vivo. 2) Evaluate the importance of IGF-1 mediated activation of ER signaling (crosstalk) in mammary tumorigenesis and in the development of tamoxifen/antiestrogen resistance in vivo. [unreadable] [unreadable]